Osteoarthritis (OA) is a chronic disease in which the articular cartilage that lies on the ends of bones that forms the articulating surface of the joints gradually degenerates over time. There are many factors that are believed to predispose a patient to osteoarthritis including genetic susceptibility, obesity, accidental or athletic trauma, surgery, drugs and heavy physical demands. Osteoarthritis is thought to be initiated by damage to the cartilage of joints. The two most common injuries to joints are sports-related injuries and long term “repetitive use” joint injuries. Joints most commonly affected by osteoarthritis are the knees, hips and hands. In most cases, due to the essential weight-bearing function of the knees and hips, osteoarthritis in these joints causes much more disability than osteoarthritis of the hands. As cartilage degeneration progresses, secondary changes occur in other tissues in and around joints including bone, muscle, ligaments, menisci and synovium. The net effect of the primary failure of cartilage tissue and secondary damage to other tissues is that the patient experiences pain, swelling, weakness and loss of functional ability in the afflicted joint(s). These symptoms frequently progress to the point that they have a significant impact in terms of lost productivity and or quality of life consequences for the patient.
Articular cartilage is predominantly composed of chondrocytes, type II collagen, proteoglycans and water. Articular cartilage has no blood or nerve supply and chondrocytes are the only type of cell in this tissue. Chondrocytes are responsible for manufacturing the type II collagen and proteoglycans that form the cartilage matrix. This matrix in turn has physical-chemical properties that allow for saturation of the matrix with water. The net effect of this structural-functional relationship is that articular cartilage has exceptional wear characteristics and allows for almost frictionless movement between the articulating cartilage surfaces. In the absence of osteoarthritis, articular cartilage often provides a lifetime of pain-free weight bearing and unrestricted joint motion even under demanding physical conditions.
Like all living tissues, articular cartilage is continually undergoing a process of renewal in which “old” cells and matrix components are being removed (catabolic activity) and “new” cells and molecules are being produced (anabolic activity). Relative to most tissues, the rate of anabolic/catabolic turnover in articular cartilage is low. Long-term maintenance of the structural integrity of mature cartilage relies on the proper balance between matrix synthesis and degradation. Chondrocytes maintain matrix equilibrium by responding to chemical and mechanical stimuli from their environment. Appropriate and effective chondrocyte responses to these stimuli are essential for cartilage homeostasis. Disruption of homeostasis through either inadequate anabolic activity or excessive catabolic activity can result in cartilage degradation and osteoarthritis (Adams et al., 1995, Nature 377 Suppl:3-174). Most tissues that are damaged and have increased catabolic activity are able to mount an increased anabolic response that allows for tissue healing. Unfortunately, chondrocytes have very limited ability to up-regulate their anabolic activity and increase the synthesis of proteoglycan and type II collagen in response to damage or loss of cartilage matrix.
Currently there is no known medical treatment to reverse the effects of this cartilage damage. Rather all current therapies for osteoarthritis are directed towards treating the symptoms. In addition, because of the insidious occurrence and slow progression of osteoarthritis, identification of osteoarthritis is often done at a late stage in disease development rather than early in disease progression when potential treatments would be more likely to be effective. As a result further advances in preventing, modifying or curing the osteoarthritic disease process critically depend on identification of early diagnostic markers of disease so as to allow early intervention.
“Early stage osteoarthritis” is currently very difficult to diagnose. The physician relies primarily on the patient's history and physical exam to make the diagnosis of mild osteoarthritis. X-rays do not show the underlying early changes in articular cartilage. Currently there are no recognized biochemical markers used to confirm the diagnosis of early stage osteoarthritis. Symptoms, such as episodic joint pain, are a common manifestation of early osteoarthritis. Joints become tender during an episode, which can last days to weeks and remit spontaneously. These symptoms, however, often do not correlate well with the pathological stages of damage to the cartilage. A more reliable measure of “early stage” osteoarthritis can be obtained by determining the extent of cartilage damage, however there is currently no method for measuring cartilage deterioration which is relatively non-invasive.
The clinical exam of a joint with “late stage” osteoarthritis reveals tenderness, joint deformity and a loss of mobility. Passive joint movement during examination may elicit crepitus or the grinding of bone-on-bone as the joint moves. X-ray changes are often profound: the joint space may be obliterated and misalignment of the joint can be seen. New bone formation (osteophytes) is prominent. Again, there are no non-invasive methods which can be used to accurately confirm the diagnosis of “late stage osteoarthritis”.
Thus there is a need for a simple non-invasive diagnostic test for detecting the various stages of osteoarthritis, and a prognostic test that effectively monitors a patient's response to therapy.